Twelve‐membered macrolactones: privileged scaffolds for the development of new therapeutics

Abstract

Natural products commonly produced as secondary metabolites of various plants and micro-organisms represent a diverse chemical space of compounds. The diversity of natural products makes them an attractive target for interrogation by both chemists and biologists alike. Indeed, the study of 12-membered macrolactones has already led to the discovery of lead drug compounds and new biological targets, which has motivated the development of diverted total synthetic routes to libraries of analogs. This review explores the discovery, biological characterization, and synthesis of several 12-membered macrolactones, exploiting examples that underscore their importance in the drug discovery field. It is our hope that this review will motivate further interest in this class of natural products, a group of molecules that we think merit the classification of 'privileged scaffolds' within the medicinal chemistry community, to further investigate and develop novel compounds with promising bioactivity. K E Y W O R D Santibiotic, biosynthesis, diverted total synthesis, macrolactone, natural product

Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F

“…Furthermore, this variation in ring sizes between known inhibitors made us wonder whether the current ring size is already optimal for each macrocycle. 27,28 However, no such SAR explorations have been reported. To address how ring size may affect the biological activity of ipomoeassin F, one of the most potent Sec61 inhibitors identified to date, we designed two new analogues (1 and 2, Figure 1) with an 18-membered and 22-membered ring, respectively.…”

Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms

“…It is well-known that slight structural modifications to macrolactones can result in significant biological outcomes; 19 for example, the simple deletion of a methyl group is enough to render a molecule inactive, as was nicely demonstrated by the Andrade lab in their syntheses of desmethyl telithromycin analogs. 20 On the basis of these prior reports, we sought to evaluate fully all desilyated compounds en route to “carylacton” to understand better the SAR of such perturbations.…”

Macrocycles, the edge of drug‐likeness chemical space or Goldilocks zone?

“…In the review by Brzozowski and Wuest, the authors argue that 12‐membered ring lactones are “privileged scaffolds” whose potential as biologically active molecules and potential drugs are still unrealized. Chemically fascinating, these structures show diverse chemistry and biological activities.…”